Abstract Alzheimer?s disease (AD) is a progressive, disabling neurodegenerative illness that affects an estimated 5.5 million people in the United States and approximately 10% of the population over the age of 65. Early symptoms of the disease include short-term memory loss, difficulties with language, and mood swings; however, symptoms gradually worsen over time, ultimately leading to dementia and a loss of bodily functions. Significant challenges exist in the diagnosis of AD. In recent years, neuron-derived exosomes (30-150 nm extracellular vesicles) have emerged as a promising biomarker for diagnosing AD. Neuron- derived exosomes are an interesting target because they are able to cross the blood-brain barrier and they contain markers that are specific to their cell of origin (i.e. neurons). As a result, neuron-derived exosomes found in circulation can provide a simple, non-invasive means of monitoring the health of the central nervous system. Accumulating evidence suggests that neuron-derived exosomes may play a crucial role in the pathology of AD by helping to spread abnormal, potentially disease-causing, misfolded proteins throughout the brain. Preliminary studies have shown that by analyzing the number of neuron-derived exosomes and their molecular cargo (such as tau, amyloid-beta, and different microRNA levels), early- stage AD patients can be distinguished from healthy controls, as well as patients with other neurological diseases. While researchers have made progress in identifying neuron-derived exosomal proteins and RNAs, difficulties surrounding the isolation and analysis of exosomes have prevented their widespread use a biomarker for AD. Currently, there are no commercially available products capable of simultaneously isolating and analyzing neuron-derived exosomes. In this SBIR Phase I project, we will address this unmet need by demonstrating the feasibility and utility of an acoustofluidic (i.e. the fusion of acoustics and microfluidics) platform for automated, high-purity, high-yield, biocompatible exosome isolation and accurate exosome analysis for AD diagnosis. With its advantages in automation, speed, precision, and accuracy, the proposed acoustofluidic technology has the potential to greatly simplify and revolutionize the diagnosis of AD. If successful, our acoustofluidic platform could be used to help standardize exosomal biomarker research and identify preclinical AD patients at early stages for future disease-altering therapies.